This recent initiative was designed to elucidate the potential uses and pitfalls of a newly recognized modality of vaccination and to extend our long-term effort to study the immune response and clinical sequela of hepatitis C virus (HCV) infection. Genetic immunization was first demonstrated in mice by directly injecting plasmids containing influenza core protein-encoding DNA into muscle. This procedure induced both antibody and cytotoxic T lymphocyte (CTL) responses to influenza, and the induced CTL can protect mice from challenge with heterologous influenza strains. One of the advantages of genetic immunization is that the endogenously expressed proteins can be recognized by class I major histocompatibility complex (MHC) molecules and expressed on the cell surface. The MHC-antigen complex on the cell surface can be recognized by CTLs, which in turn are activated and attack infected cells. The possibility of inducing an immune response to HCV core protein using DNA immunization provides an attractive alternative to classic vaccination. Many problematic issues are related to developing a vaccine for HCV. One of the major concerns is HCV's genetic stability. There are two hypervariable regions in the putative HCV envelope proteins. The immune escape mutants observed were believed to have mutated in these regions. Experimentally infected chimpanzees and HCV patients were found to have repeated bouts of infection with either homologous or new strains of HCV. This finding could be one of the reasons that more than 80 percent of the infections become chronic. Directly induced strong cell mediated immunity, especially using protective CTLs, may not only help to prevent initial HCV infection, it may even serve as an immune modulation to overcome the infection.